Delivery of antihistamines through an inhalation route

ABSTRACT

The present invention relates to the delivery of antihistamines through an inhalation route. Specifically, it relates to aerosols containing antihistamines that are used in inhalation therapy. In a method aspect of the present invention, an antihistamine is delivered to a patient through an inhalation route. The method comprises: a) heating a composition, wherein the composition comprises an antihistamine, to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles with less than 5% antihistamine drug degradation products. In a kit aspect of the present invention, a kit for delivering an antihistamine through an inhalation route is provided which comprises: a) a thin coating of an antihistamine drug composition and b) a device for dispensing said thin coating as a condensation aerosol.

This application is a continuation of U.S. patent application Ser. No.10/153,831, entitled “Delivery of Antihistamines Through an InhalationRoute,” filed May 21, 2002 now U.S. Pat. 6,740,308, Rabinowitz andZaffaroni, which claims priority to U.S. provisional application Ser.No. 60/294,203 entitled “Thermal Vapor Delivery of Drugs,” filed May 24,2001, Rabinowitz and Zaffaroni, and to U.S. provisional application Ser.No. 60/317,479 entitled “Aerosol Drug Delivery,” filed Sep. 5, 2001,Rabinowitz and Zaffaroni, the entire disclosures of which are herebyincorporated by reference.

FIELD OF THE INVENTION

The present invention relates to the delivery of antihistamines throughan inhalation route. Specifically, it relates to aerosols containingantihistamines that are used in inhalation therapy.

BACKGROUND OF THE INVENTION

There are a number of antihistamine containing compositions currentlymarketed for the treatment of allergy symptoms. The compositions containat least one active ingredient that provides for observed therapeuticeffects. Among the active ingredients in such compositions areazatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine,cyproheptadine, loratadine, pyrilamine, hydroxyzine, and promethazine.

It is desirable to provide a new route of administration forantihistamines that rapidly produces peak plasma concentrations of thecompound. The provision of such a route is an object of the presentinvention.

SUMMARY OF THE INVENTION

The present invention relates to the delivery of antihistamines throughan inhalation route. Specifically, it relates to aerosols containingantihistamines that are used in inhalation therapy.

In a composition aspect of the present invention, the aerosol comprisesparticles comprising at least 5 percent by weight of an antihistamine.Preferably, the particles comprise at least 10 percent by weight of anantihistamine. More preferably, the particles comprise at least 20percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent or99.97 percent by weight of an antihistamine.

Typically, the antihistamine is not one of the following antihistamines:dexmedetomidine, diphenhydramine, doxylamine, loratidine, andpromethazine.

Typically, the aerosol has a mass of at least 0.10 μg. Preferably, theaerosol has a mass of at least 100 μg. More preferably, the aerosol hasa mass of at least 200 μg.

Typically, the aerosol particles comprise less than 10 percent by weightof antihistamine degradation products. Preferably, the particlescomprise less than 5 percent by weight of antihistamine degradationproducts. More preferably, the particles comprise less than 2.5, 1, 0.5,0.1 or 0.03 percent by weight of antihistamine degradation products.

Typically, the aerosol particles comprise less than 90 percent by weightof water. Preferably, the particles comprise less than 80 percent byweight of water. More preferably, the particles comprise less than 70percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10percent, or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, the aerosol has an inhalable aerosol particle density greaterthan 10⁶ particles/mL. Preferably, the aerosol has an inhalable aerosolparticle density greater than 10⁷ particles/mL. More preferably, theaerosol has an inhalable aerosol particle density greater than 10⁸particles/mL.

Typically, the aerosol particles have a mass median aerodynamic diameterof less than 5 microns. Preferably, the particles have a mass medianaerodynamic diameter of less than 3 microns. More preferably, theparticles have a mass median aerodynamic diameter of less than 2 or 1micron(s). In certain embodiments the particles have an MMAD of fromabout 0.2 to about 3 microns.

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.85. Morepreferably, the geometric standard deviation is less than 2.7.

Typically, the aerosol is formed by heating a composition containing anantihistamine to form a vapor and subsequently allowing the vapor tocondense into an aerosol.

In another composition aspect of the present invention, the aerosolcomprises particles comprising at least 5 percent by weight ofazatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine,cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine.Preferably, the particles comprise at least 10 percent by weight ofazatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine,cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine.More preferably, the particles comprise at least 20 percent, 30 percent,40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent,95 percent, 97 percent, 99 percent, 99.5 percent or 99.97 percent byweight of azatadine, brompheniramine, carbinoxamine, chlorpheniramine,clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, orpromethazine.

Typically, the aerosol has a mass of at least 0.10 μg. Preferably, theaerosol has a mass of at least 100 μg. More preferably, the aerosol hasa mass of at least 200 μg.

Typically, the aerosol particles comprise less than 10 percent by weightof azatadine, brompheniramine, carbinoxamine, chlorpheniramine,clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, orpromethazine degradation products. Preferably, the particles compriseless than 5 percent by weight of azatadine, brompheniramine,carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine,pyrilamine, hydroxyzine, or promethazine degradation products. Morepreferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03percent by weight of azatadine, brompheniramine, carbinoxamine,chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine,hydroxyzine, or promethazine degradation products.

Typically, the aerosol particles comprise less than 90 percent by weightof water. Preferably, the particles comprise less than 80 percent byweight of water. More preferably, the particles comprise less than 70percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10percent, or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, where the aerosol comprises azatadine, the aerosol has aninhalable aerosol drug mass density of between 0.2 mg/L and 2.5 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 0.35 mg/L and 2 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 0.5 mg/L and 1.5 mg/L.

Typically, where the aerosol comprises clemastine, the aerosol has aninhalable aerosol drug mass density of between 0.25 mg/L and 6 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 0.35 mg/L and 4 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 0.5 mg/L and 3.5 mg/L.

Typically, where the aerosol comprises chlorpheniramine, the aerosol hasan inhalable aerosol drug mass density of between 0.5 mg/L and 5 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 0.75 mg/L and 4 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 1 mg/L and 3 mg/L.

Typically, where the aerosol comprises brompheniramine, carbinoxamine orcyproheptadine, the aerosol has an inhalable aerosol drug mass densityof between 0.8 mg/L and 10 mg/L. Preferably, the aerosol has aninhalable aerosol drug mass density of between 1.4 mg/L and 8 mg/L. Morepreferably, the aerosol has an inhalable aerosol drug mass density ofbetween 2 mg/L and 6 mg/L.

Typically, where the aerosol comprises loratadine, the aerosol has aninhalable aerosol drug mass density of between 2 mg/L and 25 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 3.5 mg/L and 20 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 5 mg/L and 15 mg/L.

Typically, where the aerosol comprises promethazine, the aerosol has aninhalable aerosol drug mass density of between 5 mg/L and 60 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 10 mg/L and 47.5 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 15 mg/L and 35 mg/L.

Typically, where the aerosol comprises pyrilamine, the aerosol has aninhalable aerosol drug mass density of between 6 mg/L and 70 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 13 mg/L and 55 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 20 mg/L and 40 mg/L.

Typically, where the aerosol comprises hydroxyzine, the aerosol has aninhalable aerosol drug mass density of between 2 mg/L and 100 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 5 mg/L and 75 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 10 mg/L and 50 mg/L.

Typically, the aerosol has an inhalable aerosol particle density greaterthan 10⁶ particles/mL. Preferably, the aerosol has an inhalable aerosolparticle density greater than 10⁷ particles/mL. More preferably, theaerosol has an inhalable aerosol particle density greater than 10⁸particles/mL.

Typically, the aerosol particles have a mass median aerodynamic diameterof less than 5 microns. Preferably, the particles have a mass medianaerodynamic diameter of less than 3 microns. More preferably, theparticles have a mass median aerodynamic diameter of less than 2 or 1micron(s).

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.85. Morepreferably, the geometric standard deviation is less than 2.7.

Typically, the aerosol is formed by heating a composition containingazatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine,cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine toform a vapor and subsequently allowing the vapor to condense into anaerosol.

In a method aspect of the present invention, an antihistamine isdelivered to a mammal through an inhalation route. The method comprises:a) heating a composition, wherein the composition comprises at least 5percent by weight of an antihistamine; and, b) allowing the vapor tocool, thereby forming a condensation aerosol comprising particles, whichis inhaled by the mammal. Preferably, the composition that is heatedcomprises at least 10 percent by weight of an antihistamine. Morepreferably, the composition comprises 20 percent, 30 percent, 40percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97percent by weight of an antihistamine.

Typically, the antihistamine is not one of the following antihistamines:dexmedetomidine, diphenhydramine, doxylamine, loratidine, andpromethazine.

In certain embodiments, the composition that is heated comprises atleast 15 percent by weight of an antihistamine pharmaceuticallyacceptable salt. Preferably, the salt is a hydrochloric acid salt,hydrobromic acid salt, acetic acid salt, maleic acid salt, formic acidsalt or fumaric acid salt.

Typically, the delivered aerosol particles comprise at least 5 percentby weight of an antihistamine. Preferably, the particles comprise atleast 10 percent by weight of an antihistamine. More preferably, theparticles comprise at least 20 percent, 30 percent, 40 percent, 50percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent byweight of an antihistamine.

Typically, the delivered aerosol has a mass of at least 10 μg.Preferably, the aerosol has a mass of at least 100 μg. More preferably,the aerosol has a mass of at least 200

Typically, the delivered aerosol particles comprise less than 10 percentby weight of antihistamine degradation products. Preferably, theparticles comprise less than 5 percent by weight of antihistaminedegradation products. More preferably, the particles comprise less than2.5, 1, 0.5, 0.1 or 0.03 percent by weight of antihistamine degradationproducts.

Typically, the particles of the delivered condensation aerosol have amass median aerodynamic diameter of less than 5 microns. Preferably, theparticles have a mass median aerodynamic diameter of less than 3microns. More preferably, the particles have a mass median aerodynamicdiameter of less than 2 or 1 micron(s).

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.85. Morepreferably, the geometric standard deviation is less than 2.7.

Typically, the particles of the delivered condensation aerosol compriseless than 90 percent by weight of water. Preferably, the particlescomprise less than 80 percent by weight of water. More preferably, theparticles comprise less than 70 percent, 60 percent, 50 percent, 40percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight ofwater.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, the delivered aerosol has an inhalable aerosol particledensity greater than 10⁶ particles/mL. Preferably, the aerosol has aninhalable aerosol particle density greater than 10⁷ particles/mL. Morepreferably, the aerosol has an inhalable aerosol particle densitygreater than 10⁸ particles/mL.

Typically, the rate of inhalable aerosol particle formation of thedelivered condensation aerosol is greater than 10⁸ particles per second.Preferably, the aerosol is formed at a rate greater than 10⁹ inhalableparticles per second. More preferably, the aerosol is formed at a rategreater than 10¹⁰ inhalable particles per second.

Typically, the delivered aerosol is formed at a rate greater than 0.25mg/second. Preferably, the aerosol is formed at a rate greater than 0.5mg/second. More preferably, the aerosol is formed at a rate greater than1 or 2 mg/second.

Typically, the delivered condensation aerosol results in a peak plasmaconcentration of the antihistamine in the mammal in less than 1 h.Preferably, the peak plasma concentration is reached in less than 0.5 h.More preferably, the peak plasma concentration is reached in less than0.2, 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterial measurement).

Typically, the delivered condensation aerosol is used to treat allergysymptoms.

In another method aspect of the present invention, azatadine,brompheniramine, carbinoxamine, chlorpheniramine, clemastine,cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine isdelivered to a mammal through an inhalation route. The method comprises:a) heating a composition, wherein the composition comprises at least 5percent by weight of azatadine, brompheniramine, carbinoxamine,chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine,hydroxyzine, or promethazine; and, b) allowing the vapor to cool,thereby forming a condensation aerosol comprising particles, which isinhaled by the mammal. Preferably, the composition that is heatedcomprises at least 10 percent by weight of azatadine, brompheniramine,carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine,pyrilamine, hydroxyzine, or promethazine. More preferably, thecomposition comprises 20 percent, 30 percent, 40 percent, 50 percent, 60percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99percent, 99.5 percent, 99.9 percent or 99.97 percent by weight ofazatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine,cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine.

In certain embodiments, the composition that is heated comprises atleast 15 percent by weight of an azatadine, brompheniramine,carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine,pyrilamine, hydroxyzine, or promethazine pharmaceutically acceptablesalt. Preferably, the salt is a hydrochloric acid salt, hydrobromic acidsalt, acetic acid salt, maleic acid salt, formic acid salt or fumaricacid salt.

Typically, the delivered aerosol particles comprise at least 5 percentby weight of azatadine, brompheniramine, carbinoxamine,chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine,hydroxyzine, or promethazine. Preferably, the particles comprise atleast 10 percent by weight of azatadine, brompheniramine, carbinoxamine,chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine,hydroxyzine, or promethazine. More preferably, the particles comprise atleast 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent,99.5 percent, 99.9 percent or 99.97 percent by weight of azatadine,brompheniramine, carbinoxamine, chlorpheniramine, clemastine,cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine.

Typically, the delivered aerosol has a mass of at least 10 μg.Preferably, the aerosol has a mass of at least 100 μg. More preferably,the aerosol has a mass of at least 200 μg.

Typically, the delivered aerosol particles comprise less than 10 percentby weight of azatadine, brompheniramine, carbinoxamine,chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine,hydroxyzine, or promethazine degradation products. Preferably, theparticles comprise less than 5 percent by weight of azatadine,brompheniramine, carbinoxamine, chlorpheniramine, clemastine,cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazinedegradation products. More preferably, the particles comprise less than2.5, 1, 0.5, 0.1 or 0.03 percent by weight of azatadine,brompheniramine, carbinoxamine, chlorpheniramine, clemastine,cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazinedegradation products.

Typically, the particles of the delivered condensation aerosol have amass median aerodynamic diameter of less than 5 microns. Preferably, theparticles have a mass median aerodynamic diameter of less than 3microns. More preferably, the particles have a mass median aerodynamicdiameter of less than 2 or 1 micron(s).

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.85. Morepreferably, the geometric standard deviation is less than 2.7.

Typically, the particles of the delivered condensation aerosol compriseless than 90 percent by weight of water. Preferably, the particlescomprise less than 80 percent by weight of water. More preferably, theparticles comprise less than 70 percent, 60 percent, 50 percent, 40percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight ofwater.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, where the aerosol comprises azatadine, the aerosol has aninhalable aerosol drug mass density of between 0.2 mg/L and 2.5 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 0.35 mg/L and 2 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 0.5 mg/L and 1.5 mg/L.

Typically, where the aerosol comprises clemastine, the aerosol has aninhalable aerosol drug mass density of between 0.25 mg/L and 6 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 0.35 mg/L and 4 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 0.5 mg/L and 3.5 mg/L.

Typically, where the aerosol comprises chlorpheniramine, the aerosol hasan inhalable aerosol drug mass density of between 0.5 mg/L and 5 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 0.75 mg/L and 4 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 1 mg/L and 3 mg/L.

Typically, where the aerosol comprises brompheniramine, carbinoxamine orcyproheptadine, the aerosol has an inhalable aerosol drug mass densityof between 0.8 mg/L and 10 mg/L. Preferably, the aerosol has aninhalable aerosol drug mass density of between 1.4 mg/L and 8 mg/L. Morepreferably, the aerosol has an inhalable aerosol drug mass density ofbetween 2 mg/L and 6 mg/L.

Typically, where the aerosol comprises loratadine, the aerosol has aninhalable aerosol drug mass density of between 2 mg/L and 25 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 3.5 mg/L and 20 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 5 mg/L and 15 mg/L.

Typically, where the aerosol comprises promethazine, the aerosol has aninhalable aerosol drug mass density of between 5 mg/L and 60 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 10 mg/L and 47.5 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 15 mg/L and 35 mg/L.

Typically, where the aerosol comprises hydroxyzine, the aerosol has aninhalable aerosol drug mass density of between 2 mg/L and 100 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 5 mg/L and 75 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 10 mg/L and 50 mg/L.

Typically, where the aerosol comprises pyrilamine, the aerosol has aninhalable aerosol drug mass density of between 6 mg/L and 70 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 13 mg/L and 55 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 20 mg/L and 40 mg/L.

Typically, the delivered aerosol has an inhalable aerosol particledensity greater than 10⁶ particles/mL. Preferably, the aerosol has aninhalable aerosol particle density greater than 10⁷ particles/mL. Morepreferably, the aerosol has an inhalable aerosol particle densitygreater than 10⁸ particles/mL.

Typically, the rate of inhalable aerosol particle formation of thedelivered condensation aerosol is greater than 10⁸ particles per second.Preferably, the aerosol is formed at a rate greater than 10⁹ inhalableparticles per second. More preferably, the aerosol is formed at a rategreater than 10¹⁰ inhalable particles per second.

Typically, the delivered aerosol is formed at a rate greater than 0.25mg/second. Preferably, the aerosol is formed at a rate greater than 0.5mg/second. More preferably, the aerosol is formed at a rate greater than1 or 2 mg/second.

Typically, where the aerosol comprises azatadine, between 0.2 mg and 2.5mg of azatadine is delivered to the mammal in a single inspiration.Preferably, between 0.35 mg and 2 mg of azatadine is delivered to themammal in a single inspiration. More preferably, between 0.5 mg and 1.5mg of azatadine is delivered to the mammal in a single inspiration.

Typically, where the aerosol comprises clemastine, between 0.25 mg and 6mg of clemastine is delivered to the mammal in a single inspiration.Preferably, between 0.35 mg and 4 mg of clemastine is delivered to themammal in a single inspiration. More preferably, between 0.5 mg and 3.5mg of clemastine is delivered to the mammal in a single inspiration.

Typically, where the aerosol comprises chlorpheniramine, between 0.5 mgand 5 mg of chlorpheniramine is delivered to the mammal in a singleinspiration. Preferably, between 0.75 mg and 4 mg of chlorpheniramine isdelivered to the mammal in a single inspiration. More preferably,between 1 mg and 3 mg of chlorpheniramine is delivered to the mammal ina single inspiration.

Typically, where the aerosol comprises brompheniramine, carbinoxamine orcyproheptadine, between 0.8 mg and 10 mg of brompheniramine,carbinoxamine or cyproheptadine is delivered to the mammal in a singleinhalation. Preferably, between 1.4 mg and 8 mg of brompheniramine,carbinoxamine or cyproheptadine is delivered to the mammal in a singleinhalation. More preferably, between 2 mg and 6 mg of brompheniramine,carbinoxamine or cyproheptadine is delivered to the mammal in a singleinhalation.

Typically, where the aerosol comprises loratadine, between 2 mg and 25mg or loratadine is delivered to the mammal in a single inhalation.Preferably, between 3.5 mg and 20 mg of loratadine is delivered to themammal in a single inspiration. More preferably, between 5 mg and 15 mgof loratadine is delivered to the mammal in a single inspiration.

Typically, where the aerosol comprises promethazine, between 5 mg and 60mg of promethazine is delivered to the mammal in a single inspiration.Preferably, between 10 mg and 47.5 mg of promethazine is delivered tothe mammal in a single inspiration. More preferably, between 15 mg and35 mg of promethazine is delivered to the mammal in a singleinspiration.

Typically, where the aerosol comprises hydroxyzine, between 2 mg and 100mg of hydroxyzine is delivered to the mammal in a single inspiration.Preferably, between 5 mg and 75 mg of hydroxyzine is delivered to themammal in a single inspiration. More preferably, between 10 mg and 50 mgof hydroxyzine is delivered to the mammal in a single inspiration.

Typically, where the aerosol comprises pyrilamine, between 6 mg and 70mg of pyrilamine is delivered to the mammal in a single inspiration.Preferably, between 13 mg and 55 mg of pyrilamine is delivered to themammal in a single inspiration. More preferably, between 20 mg and 40 mgof pyrilamine is delivered to the mammal in a single inspiration.

Typically, the delivered condensation aerosol results in a peak plasmaconcentration of azatadine, brompheniramine, carbinoxamine,chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine,hydroxyzine, or promethazine in the mammal in less than 1 h. Preferably,the peak plasma concentration is reached in less than 0.5 h. Morepreferably, the peak plasma concentration is reached in less than 0.2,0.1, 0.05, 0.02, 0.01, or 0.005 h (arterial measurement).

Typically, the delivered condensation aerosol is used to treat allergysymptoms.

In a kit aspect of the present invention, a kit for delivering anantihistamine through an inhalation route to a mammal is provided whichcomprises: a) a composition comprising at least 5 percent by weight ofan antihistamine; and, b) a device that forms an antihistaminecontaining aerosol from the composition, for inhalation by the mammal.Preferably, the composition comprises at least 10 percent by weight ofan antihistamine. More preferably, the composition comprises at least 20percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent,99.9 percent or 99.97 percent by weight of an antihistamine.

Typically, the device contained in the kit comprises: a) an element forheating the antihistamine composition to form a vapor; b) an elementallowing the vapor to cool to form an aerosol; and, c) an elementpermitting the mammal to inhale the aerosol.

In another kit aspect of the present invention, a kit for deliveringazatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine,cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine aninhalation route to a mammal is provided which comprises: a) acomposition comprising at least 5 percent by weight of azatadine,brompheniramine, carbinoxamine, chlorpheniramine, clemastine,cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine;and, b) a device that forms a azatadine, brompheniramine, carbinoxamine,chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine,hydroxyzine, or promethazine containing aerosol from the composition,for inhalation by the mammal. Preferably, the composition comprises atleast 10 percent by weight of azatadine, brompheniramine, carbinoxamine,chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine,hydroxyzine, or promethazine. More preferably, the composition comprisesat least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent,99.5 percent, 99.9 percent or 99.97 percent by weight of azatadine,brompheniramine, carbinoxamine, chlorpheniramine, clemastine,cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine.

Typically, the device contained in the kit comprises: a) an element forheating the azatadine, brompheniramine, carbinoxamine, chlorpheniramine,clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, orpromethazine composition to form a vapor; b) an element allowing thevapor to cool to form an aerosol; and, c) an element permitting themammal to inhale the aerosol.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 shows a device used to deliver antihistamine containing aerosolsto a mammal through an inhalation route.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

“Aerodynamic diameter” of a given particle refers to the diameter of aspherical droplet with a density of 1 g/mL (the density of water) thathas the same settling velocity as the given particle.

“Aerosol” refers to a suspension of solid or liquid particles in a gas.

“Aerosol drug mass density” refers to the mass of antihistamine per unitvolume of aerosol.

“Aerosol mass density” refers to the mass of particulate matter per unitvolume of aerosol.

“Aerosol particle density” refers to the number of particles per unitvolume of aerosol.

“Amorphous particle” refers to a particle that does not contain morethan 50 percent by weight of a crystalline form. Preferably, theparticle does not contain more than 25 percent by weight of acrystalline form. More preferably, the particle does not contain morethan 10 percent by weight of a crystalline form.

“Antihistamine degradation product” refers to a compound resulting froma chemical modification of an antihistamine. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

“Azatadine” refers to6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine.

“Azatadine degradation product” refers to a compound resulting from achemical modification of azatadine. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Brompheniramine” refers to1-(p-bromophenyl)-1-(2-pyridyl)-3-N,N-dimethylaminopropane.

“Brompheniramine degradation product” refers to a compound resultingfrom a chemical modification of brompheniramine. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

“Carbinoxamine” refers to2-[p-chloro-α-(2-dimethylaminoethoxy)benzyl]-pyridine.

“Carbinoxamine degradation product” refers to a compound resulting froma chemical modification of carbinoxamine. The modification, for example,can be the result of a thermally or photochemically induced reaction.Such reactions include, without limitation, oxidation and hydrolysis.

“Chlorpheniramine” refers to1-(p-chlorophenyl)-1-(2-pyridyl)-3-N,N-dimethylaminopropane.

“Chlorpheniramine degradation product” refers to a compound resultingfrom a chemical modification of chlorpheniramine. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis. An example of a degradation product is a compound ofmolecular formula C₁₂H₈NOCl.

“Clemastine” refers to2-[2-[1-(4-chlorophenyl)-1-phenyl-ethoxy]ethyl]-1-methylpyrrolidine.

“Clemastine degradation product” refers to a compound resulting from achemical modification of clemastine. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis. Anexample of a degradation product is C₁₄H₁₃OCl (removal of sidechain fromoxygen, yielding an alcohol).

“Condensation aerosol” refers to an aerosol formed by vaporization of asubstance followed by condensation of the substance into an aerosol.

“Cyproheptadine” refers to4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine.

“Cyproheptadine degradation product” refers to a compound resulting froma chemical modification of cyproheptadine. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis. An example of a degradation product is the N-oxide ofcyproheptadine (C₂₁H₂₁NO).

“Hydroxyzine” refers to2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethoxy]ethanol.

“Hydroxyzine degradation product” refers to a compound resulting from achemical modification of hydroxyzine. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis. Anexample of a degradation product is a compound of molecular formulaC₁₃H₉OCl (a chloro benzophenone).

“Inhalable aerosol drug mass density” refers to the aerosol drug massdensity produced by an inhalation device and delivered into a typicalpatient tidal volume.

“Inhalable aerosol mass density” refers to the aerosol mass densityproduced by an inhalation device and delivered into a typical patienttidal volume.

“Inhalable aerosol particle density” refers to the aerosol particledensity of particles of size between 100 nm and 5 microns produced by aninhalation device and delivered into a typical patient tidal volume.

“Loratadine” refers to ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridine-11-ylidene)-1-piperidinecarboxylate

“Loratadine degradation product” refers to a compound resulting from achemical modification of loratadine. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Mass median aerodynamic diameter” or “MMAD” of an aerosol refers to theaerodynamic diameter for which half the particulate mass of the aerosolis contributed by particles with an aerodynamic diameter larger than theMMAD and half by particles with an aerodynamic diameter smaller than theMMAD.

“Promethazine” refers to 10-(2-dimethylaminopropyl)phenothiazine.

“Promethazine degradation product” refers to a compound resulting from achemical modification of promethazine. The modification, for example,can be the result of a thermally or photochemically induced reaction.Such reactions include, without limitation, oxidation and hydrolysis. Anexample of a degradation product is a compound of molecular formulaC₁₂H₉NOS (a sulfoxide).

“Pyrilamine” refers toN-[(4-methoxyphenyl)methyl]-N′,N′-dimethyl-N-2-pyridinyl-1,2-ethanediamine.

“Pyrilamine degradation product” refers to a compound resulting from achemical modification of pyrilamine. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis. Anexample of a degradation product is 4-methoxy-benzaldehyde.

“Rate of aerosol formation” refers to the mass of aerosolizedparticulate matter produced by an inhalation device per unit time.

“Rate of inhalable aerosol particle formation” refers to the number ofparticles of size between 100 nm and 5 microns produced by an inhalationdevice per unit time.

“Rate of drug aerosol formation” refers to the mass of aerosolizedantihistamine produced by an inhalation device per unit time.

“Settling velocity” refers to the terminal velocity of an aerosolparticle undergoing gravitational settling in air.

“Typical patient tidal volume” refers to 1 L for an adult patient and 15mL/kg for a pediatric patient.

“Vapor” refers to a gas, and “vapor phase” refers to a gas phase. Theterm “thermal vapor” refers to a vapor phase, aerosol, or mixture ofaerosol-vapor phases, formed preferably by heating.

Formation of Antihistamine Containing Aerosols

Any suitable method is used to form the aerosols of the presentinvention. A preferred method, however, involves heating a compositioncomprising an antihistamine to form a vapor, followed by cooling of thevapor such that it condenses to provide an antihistamine comprisingaerosol (condensation aerosol). The composition is heated in one of fourforms: as pure active compound (e.g., pure azatadine, brompheniramine,carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine,pyrilamine, hydroxyzine, or promethazine); as a mixture of activecompound and a pharmaceutically acceptable excipient; as a salt form ofthe pure active compound; and, as a mixture of active compound salt formand a pharmaceutically acceptable excipient.

Salt forms of antihistamines (e.g., azatadine, brompheniramine,carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine,pyrilamine, hydroxyzine, or promethazine) are either commerciallyavailable or are obtained from the corresponding free base using wellknown methods in the art. A variety of pharmaceutically acceptable saltsare suitable for aerosolization. Such salts include, without limitation,the following: hydrochloric acid, hydrobromic acid, acetic acid, maleicacid, formic acid, and fumaric acid salts.

Pharmaceutically acceptable excipients may be volatile or nonvolatile.Volatile excipients, when heated, are concurrently volatilized,aerosolized and inhaled with the antihistamine. Classes of suchexcipients are known in the art and include, without limitation,gaseous, supercritical fluid, liquid and solid solvents. The followingis a list of exemplary carriers within the classes: water; terpenes,such as menthol; alcohols, such as ethanol, propylene glycol, glyceroland other similar alcohols; dimethylformamide; dimethylacetamide; wax;supercritical carbon dioxide; dry ice; and mixtures thereof.

Solid supports on which the composition is heated are of a variety ofshapes. Examples of such shapes include, without limitation, cylindersof less than 1.0 mm in diameter, boxes of less than 1.0 mm thickness andvirtually any shape permeated by small (e.g., less than 1.0 mm-sized)pores. Preferably, solid supports provide a large surface to volumeratio (e.g., greater than 100 per meter) and a large surface to massratio (e.g., greater than 1 cm² per gram).

A solid support of one shape can also be transformed into another shapewith different properties. For example, a flat sheet of 0.25 mmthickness has a surface to volume ratio of approximately 8,000 permeter. Rolling the sheet into a hollow cylinder of 1 cm diameterproduces a support that retains the high surface to mass ratio of theoriginal sheet but has a lower surface to volume ratio (about 400 permeter).

A number of different materials are used to construct the solidsupports. Classes of such materials include, without limitation, metals,inorganic materials, carbonaceous materials and polymers. The followingare examples of the material classes: aluminum, silver, gold, stainlesssteel, copper and tungsten; silica, glass, silicon and alumina;graphite, porous carbons, carbon yarns and carbon felts;polytetrafluoroethylene and polyethylene glycol. Combinations ofmaterials and coated variants of materials are used as well.

Where aluminum is used as a solid support, aluminum foil is a suitablematerial. Examples of silica, alumina and silicon based materialsinclude amphorous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (analumina of defined surface area greater than 2 m²/g from Aldrich, St.Louis, Mo.) and a silicon wafer as used in the semiconductor industry.Carbon yarns and felts are available from American Kynol, Inc., NewYork, N.Y. Chromatography resins such as octadecycl silane chemicallybonded to porous silica are exemplary coated variants of silica.

The heating of the antihistamine compositions is performed using anysuitable method. Examples of methods by which heat can be generatedinclude the following: passage of current through an electricalresistance element; absorption of electromagnetic radiation, such asmicrowave or laser light; and, exothermic chemical reactions, such asexothermic salvation, hydration of pyrophoric materials and oxidation ofcombustible materials.

Delivery of Antihistamine Containing Aerosols

Antihistamine containing aerosols of the present invention are deliveredto a mammal using an inhalation device. Where the aerosol is acondensation aerosol, the device has at least three elements: an elementfor heating an antihistamine containing composition to form a vapor; anelement allowing the vapor to cool, thereby providing a condensationaerosol; and, an element permitting the mammal to inhale the aerosol.Various suitable heating methods are described above. The element thatallows cooling is, in it simplest form, an inert passageway linking theheating means to the inhalation means. The element permitting inhalationis an aerosol exit portal that forms a connection between the coolingelement and the mammal's respiratory system.

One device used to deliver an antihistamine containing aerosol isdescribed in reference to FIG. 1. Delivery device 100 has a proximal end102 and a distal end 104, a heating module 106, a power source 108, anda mouthpiece 110. An antihistamine composition is deposited on a surface112 of heating module 106. Upon activation of a user activated switch114, power source 108 initiates heating of heating module 106 (e.g,through ignition of combustible fuel or passage of current through aresistive heating element). The antihistamine composition volatilizesdue to the heating of heating module 106 and condenses to form acondensation aerosol prior to reaching the mouthpiece 110 at theproximal end of the device 102. Air flow traveling from the devicedistal end 104 to the mouthpiece 110 carries the condensation aerosol tothe mouthpiece 110, where it is inhaled by the mammal.

Devices, if desired, contain a variety of components to facilitate thedelivery of antihistamine containing aerosols. For instance, the devicemay include any component known in the art to control the timing of drugaerosolization relative to inhalation (e.g., breath-actuation), toprovide feedback to patients on the rate and/or volume of inhalation, toprevent excessive use (i.e., “lock-out” feature), to prevent use byunauthorized individuals, and/or to record dosing histories.

Dosage of Antihistamine Containing Aerosols

The dosage amount of antihistamine in aerosol form is generally nogreater than twice the standard dose of the drug given orally. Forinstance, for the treatment of allergy symptoms azatadine,brompheniramine, carbinoxamine, chlorpheniramine, clemastine,cyproheptadine, loratadine, pyrilamine, hydroxyzine and promethazine aretypically provided orally at the following respective strengths: 1 mg, 4mg, 4 mg, 2 mg, 1.34 mg, 4 mg, 10 mg, 30 mg, 25 mg, and 25 mg. Asaerosols, the compounds are generally provided in the following amountsper inspiration for the same indication: azatadine, 0.2 mg to 2.5 mg;clemastine, 0.25 mg to 6 mg; chlorpheniramine, 0.5 mg to 5 mg;brompheniramine, 0.8 mg to 10 mg; carbinoxamine, 0.8 mg to 10 mg;cyproheptadine, 0.8 mg to 10 mg; loratadine, 2 mg to 25 mg;promethazine, 5 mg to 60 mg; hydroxyzine, 2 mg to 100 mg; and,pyrilamine, 6 mg to 70 mg. A typical dosage of an antihistamine aerosolis either administered as a single inhalation or as a series ofinhalations taken within an hour or less (dosage equals sum of inhaledamounts). Where the drug is administered as a series of inhalations, adifferent amount may be delivered in each inhalation.

One can determine the appropriate dose of an antihistamine containingaerosol to treat a particular condition using methods such as animalexperiments and a dose-finding (Phase I/II) clinical trial. One animalexperiment involves measuring plasma concentrations of drug in an animalafter its exposure to the aerosol. Mammals such as dogs or primates aretypically used in such studies, since their respiratory systems aresimilar to that of a human. Initial dose levels for testing in humans isgenerally less than or equal to the dose in the mammal model thatresulted in plasma drug levels associated with a therapeutic effect inhumans. Dose escalation in humans is then performed, until either anoptimal therapeutic response is obtained or a dose-limiting toxicity isencountered.

Analysis of Antihistamine Containing Aerosols

Purity of an antihistamine containing aerosol is determined using anumber of methods, examples of which are described in Sekine et al.,Journal of Forensic Science 32:1271–1280 (1987) and Martin et al.,Journal of Analytic Toxicology 13:158–162 (1989). One method involvesforming the aerosol in a device through which a gas flow (e.g., airflow) is maintained, generally at a rate between 0.4 and 60 L/min. Thegas flow carries the aerosol into one or more traps. After isolationfrom the trap, the aerosol is subjected to an analytical technique, suchas gas or liquid chromatography, that permits a determination ofcomposition purity.

A variety of different traps are used for aerosol collection. Thefollowing list contains examples of such traps: filters; glass wool;impingers; solvent traps, such as dry ice-cooled ethanol, methanol,acetone and dichloromethane traps at various pH values; syringes thatsample the aerosol; empty, low-pressure (e.g., vacuum) containers intowhich the aerosol is drawn; and, empty containers that fully surroundand enclose the aerosol generating device. Where a solid such as glasswool is used, it is typically extracted with a solvent such as ethanol.The solvent extract is subjected to analysis rather than the solid(i.e., glass wool) itself. Where a syringe or container is used, thecontainer is similarly extracted with a solvent.

The gas or liquid chromatograph discussed above contains a detectionsystem (i.e., detector). Such detection systems are well known in theart and include, for example, flame ionization, photon absorption andmass spectrometry detectors. An advantage of a mass spectrometrydetector is that it can be used to determine the structure ofantihistamine degradation products.

Particle size distribution of an antihistamine containing aerosol isdetermined using any suitable method in the art (e.g., cascadeimpaction). An Andersen Eight Stage Non-viable Cascade Impactor(Andersen Instruments, Smyrna, Ga.) linked to a furnace tube by a mockthroat (USP throat, Andersen Instruments, Smyrna, Ga.) is one systemused for cascade impaction studies.

Inhalable aerosol mass density is determined, for example, by deliveringa drug-containing aerosol into a confined chamber via an inhalationdevice and measuring the mass collected in the chamber. Typically, theaerosol is drawn into the chamber by having a pressure gradient betweenthe device and the chamber, wherein the chamber is at lower pressurethan the device. The volume of the chamber should approximate the tidalvolume of an inhaling patient.

Inhalable aerosol drug mass density is determined, for example, bydelivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the amount of active drug compoundcollected in the chamber. Typically, the aerosol is drawn into thechamber by having a pressure gradient between the device and thechamber, wherein the chamber is at lower pressure than the device. Thevolume of the chamber should approximate the tidal volume of an inhalingpatient. The amount of active drug compound collected in the chamber isdetermined by extracting the chamber, conducting chromatographicanalysis of the extract and comparing the results of the chromatographicanalysis to those of a standard containing known amounts of drug.

Inhalable aerosol particle density is determined, for example, bydelivering aerosol phase drug into a confined chamber via an inhalationdevice and measuring the number of particles of given size collected inthe chamber. The number of particles of a given size may be directlymeasured based on the light-scattering properties of the particles.Alternatively, the number of particles of a given size may be determinedby measuring the mass of particles within the given size range andcalculating the number of particles based on the mass as follows: Totalnumber of particles=Sum (from size range 1 to size range N) of number ofparticles in each size range. Number of particles in a given sizerange=Mass in the size range/Mass of a typical particle in the sizerange. Mass of a typical particle in a given size range=π*D³*φ/6, whereD is a typical particle diameter in the size range (generally, the meanboundary MMADs defining the size range) in microns, (φ is the particledensity (in g/mL) and mass is given in units of picograms (g⁻¹²).

Rate of inhalable aerosol particle formation is determined, for example,by delivering aerosol phase drug into a confined chamber via aninhalation device. The delivery is for a set period of time (e.g., 3 s),and the number of particles of a given size collected in the chamber isdetermined as outlined above. The rate of particle formation is equal tothe number of 100 nm to 5 micron particles collected divided by theduration of the collection time.

Rate of aerosol formation is determined, for example, by deliveringaerosol phase drug into a confined chamber via an inhalation device. Thedelivery is for a set period of time (e.g., 3 s), and the mass ofparticulate matter collected is determined by weighing the confinedchamber before and after the delivery of the particulate matter. Therate of aerosol formation is equal to the increase in mass in thechamber divided by the duration of the collection time. Alternatively,where a change in mass of the delivery device or component thereof canonly occur through release of the aerosol phase particulate matter, themass of particulate matter may be equated with the mass lost from thedevice or component during the delivery of the aerosol. In this case,the rate of aerosol formation is equal to the decrease in mass of thedevice or component during the delivery event divided by the duration ofthe delivery event.

Rate of drug aerosol formation is determined, for example, by deliveringan antihistamine containing aerosol into a confined chamber via aninhalation device over a set period of time (e.g., 3 s). Where theaerosol is pure antihistamine, the amount of drug collected in thechamber is measured as described above. The rate of drug aerosolformation is equal to the amount of antihistamine collected in thechamber divided by the duration of the collection time. Where theantihistamine containing aerosol comprises a pharmaceutically acceptableexcipient, multiplying the rate of aerosol formation by the percentageof antihistamine in the aerosol provides the rate of drug aerosolformation.

Utility of Antihistamine Containing Aerosols

Antihistamine containing aerosols are typically used for the treatmentof allergy symptoms.

The following examples are meant to illustrate, rather than limit, thepresent invention.

Hydroxyzine dihydrochloride, brompheniramine maleate, carbinoxaminemaleate, clemastine fumarate, cyproheptadine hydrochloride, pyrilaminemaleate, and promethazine hydrochloride are commercially available fromSigma (www.sigma-aldrich.com). Antihistamines can also be isolated fromcompositions such as RYNATAN®, DIMETANE®, RONDEC®, SINUTAB®, TAVIST®,PERIACTIN®, CLARITIN®, RYNA-12™, and PHENERGAN® using standard methodsin the art.

EXAMPLE 1 General Procedure for Obtaining Free Base of an AntihistamineSalt

Approximately 1 g of salt (e.g., mono hydrochloride) is dissolved indeionized water (˜30 mL). Three equivalents of sodium hydroxide (1 NNaOH_(aq)) is added dropwise to the solution, and the pH is checked toensure it is basic. The aqueous solution is extracted four times withdichloromethane (˜50 mL), and the extracts are combined, dried (Na₂SO₄)and filtered. The filtered organic solution is concentrated using arotary evaporator to provide the desired free base. If necessary,purification of the free base is performed using standard methods suchas chromatography or recrystallization.

EXAMPLE 2 General Procedure for Volatilizing Compounds

A solution of drug in approximately 120 μL dichloromethane is coated ona 3 cm×8 cm piece of aluminum foil. The dichloromethane is allowed toevaporate. The coated foil is wrapped around a 300 watt halogen tube(Feit Electric Company, Pico Rivera, Calif.), which is inserted into aglass tube sealed at one end with a rubber stopper. Running 60 V ofalternating current (driven by line power controlled by a variac)through the bulb for 5–11 s affords thermal vapor (including aerosol),which is collected on the glass tube walls. Reverse-phase HPLC analysiswith detection by absorption of 225 nm light is used to determine thepurity of the aerosol. (When desired, the system is flushed through withargon prior to volatilization.)

Table 1, which follows, provides data from drugs volatilized using theabove-recited general procedure. Current is typically run for 5 s afteran aerosol is first noticed. To obtain higher purity aerosols, one cancoat a lesser amount of drug, yielding a thinner film to heat. A lineardecrease in film thickness is associated with a linear decrease inimpurities.

TABLE 1 Compound Aerosol Purity Argon Used Azatadine 99.6% NoBrompheniramine 99.0% No Brompheniramine 99.3% Yes Brompheniramine 99.6%No Maleate Brompheniramine  100% Yes Maleate Carbinoxamine 94.8% YesCarbinoxamine 99.0% No Maleate Carbinoxamine  100% Yes MaleateChlorpheniramine 98.4% No Chlorpheniramine 99.6% No MaleateChlorpheniramine  100% Yes Clemastine 94.3% No Cyproheptadine  100% NoCyproheptadine 99.6% No Hydroxyzine 98.6% No Loratadine 99.0% NoLoratadine 99.6% Yes Pyrilamine 98.8% No Pyrilamine 99.5% YesPromethazine 94.5% Yes

EXAMPLE 3 Particle Size, Particle Density, and Rate of InhalableParticle Formation of Loratadine Aerosol

A solution of 12.1 mg loratadine in 200 μL dichloromethane was spreadout in a thin layer on the central portion of a 3.5 cm×7 cm sheet ofaluminum foil. The dichloromethane was allowed to evaporate. Assuming adrug density of about 1 g/cc, the calculated thickness of the loratadinethin layer on the 24.5 cm² aluminum solid support, after solventevaporation, is about 4.9 microns. The aluminum foil was wrapped arounda 300 watt halogen tube, which was inserted into a T-shaped glass tube.Both of the openings of the tube were left open and the third openingwas connected to a 1 liter, 3-neck glass flask. The glass flask wasfurther connected to a large piston capable of drawing 1.1 liters of airthrough the flask. Alternating current was run through the halogen bulbby application of 90 V using a variac connected to 110 V line power.Within 1 s, an aerosol appeared and was drawn into the 1 L flask by useof the piston, with collection of the aerosol terminated after 6 s. Theaerosol was analyzed by connecting the 1 L flask to an eight-stageAndersen non-viable cascade impactor. Results are shown in table 1. MMADof the collected aerosol was 1.1 microns with a geometric standarddeviation of 2.6. Also shown in table 1 is the number of particlescollected on the various stages of the cascade impactor, given by themass collected on the stage divided by the mass of a typical particletrapped on that stage. The mass of a single particle of diameter D isgiven by the volume of the particle, πD³/6, multiplied by the density ofthe drug (taken to be 1 g/cm³). The inhalable aerosol particle densityis the sum of the numbers of particles collected on impactor stages 3 to8 divided by the collection volume of 1 L, giving an inhalable aerosolparticle density of 5.2×10⁷ particles/mL. The rate of inhalable aerosolparticle formation is the sum of the numbers of particles collected onimpactor stages 3 through 8 divided by the formation time of 6 s, givinga rate of inhalable aerosol particle formation of 8.7×10⁹particles/second.

TABLE 1 Determination of the characteristics of a loratadinecondensation aerosol by cascade impaction using an Andersen 8-stagenon-viable cascade impactor run at 1 cubic foot per minute air flow.Mass Particle size Average particle collected Number of Stage range(microns) size (microns) (mg) particles 0  9.0–10.0 9.5 0.0 0 1 5.8–9.07.4 0.1 4.7 × 10⁵ 2 4.7–5.8 5.25 0.0 0 3 3.3–4.7 4.0 0.1 3.0 × 10⁶ 42.1–3.3 2.7 0.6 5.8 × 10⁷ 5 1.1–2.1 1.6 0.0 0 6 0.7–1.1 0.9 0.4 1.1 ×10⁹ 7 0.4–0.7 0.55 0.3 3.4 × 10⁹ 8   0–0.4 0.2 0.2  4.8 × 10¹⁰

EXAMPLE 4 Drug Mass Density and Rate of Drug Aerosol Formation ofLoratadine Aerosol

A solution of 10.4 mg loratadine in 200 μL dichloromethane was spreadout in a thin layer on the central portion of a 3.5 cm×7 cm sheet ofaluminum foil. The dichloromethane was allowed to evaporate. Assuming adrug density of about 1 g/cc, the calculated thickness of the loratadinethin layer on the 24.5 cm² aluminum solid support, after solventevaporation, is about 4.2 microns. The aluminum foil was wrapped arounda 300 watt halogen tube, which was inserted into a T-shaped glass tube.Both of the openings of the tube were left open and the third openingwas connected to a 1 liter, 3-neck glass flask. The glass flask wasfurther connected to a large piston capable of drawing 1.1 liters of airthrough the flask. Alternating current was run through the halogen bulbby application of 90 V using a variac connected to 110 V line power.Within seconds, an aerosol appeared and was drawn into the 1 L flask byuse of the piston, with formation of the aerosol terminated after 6 s.The aerosol was allowed to sediment onto the walls of the 1 L flask forapproximately 30 minutes. The flask was then extracted with acetonitrileand the extract analyzed by HPLC with detection by light absorption at225 nm. Comparison with standards containing known amounts of loratadinerevealed that 1.0 mg of >99% pure loratadine had been collected in theflask, resulting in an aerosol drug mass density of 1.0 mg/L. Thealuminum foil upon which the loratadine had previously been coated wasweighed following the experiment. Of the 10.4 mg originally coated onthe aluminum, 3.8 mg of the material was found to have aerosolized inthe 6 s time period, implying a rate of drug aerosol formation of 0.6mg/s.

1. A method of treating allergy symptoms in a patient comprisingadministering a therapeutic amount of a drug condensation aerosol to thepatient by inhalation, wherein the drug is selected from the groupconsisting of azatadine, brompheniramine, carbinoxamine,chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine,hydroxyzine and promethazine, and wherein the condensation aerosol isformed by heating a thin layer containing the drug, on a solid support,to produce a vapor of the drug, and condensing the vapor to form acondensation aerosol characterized by less than 10% drug degradationproducts by weight, and an MMAD of less than 5 microns.
 2. The methodaccording to claim 1, wherein the condensation aerosol is characterizedby an MMAD of less than 3 microns.
 3. The method according to claim 1,wherein peak plasma drug concentration is reached in less than 0.1hours.
 4. The method according to claim 1, wherein the condensationaerosol is formed at a rate greater than 0.5 mg/second.
 5. The methodaccording to claim 1, wherein at least 50% by weight of the condensationaerosol is amorphous in form.
 6. The method according to claim 1,wherein the therapeutic amount of a drug condensation aerosol comprisesbetween 0.2 mg and 2.5 mg of azatadine delivered in a singleinspiration.
 7. The method according to claim 1, wherein the therapeuticamount of a drug condensation aerosol comprises between 0.8 mg and 10 mgof brompheniramine delivered in a single inspiration.
 8. The methodaccording to claim 1, wherein the therapeutic amount of a drugcondensation aerosol comprises between 0.8 mg and 10 mg of carbinoxaminedelivered in a single inspiration.
 9. The method according to claim 1,wherein the therapeutic amount of a drug condensation aerosol comprisesbetween 0.5 mg and 5 mg of chlorpheniramine delivered in a singleinspiration.
 10. The method according to claim 1, wherein thetherapeutic amount of a drug condensation aerosol comprises between 0.25mg and 6 mg of clemastine delivered in a single inspiration.
 11. Themethod according to claim 1, wherein the therapeutic amount of a drugcondensation aerosol comprises between 0.8 mg and 10 mg ofcyproheptadine delivered in a single inspiration.
 12. The methodaccording to claim 1, wherein the therapeutic amount of a drugcondensation aerosol comprises between 2 mg and 25 mg of loratadinedelivered in a single inspiration.
 13. The method according to claim 1,wherein the therapeutic amount of a drug condensation aerosol comprisesbetween 6 mg and 70 mg of pyrilamine delivered in a single inspiration.14. The method according to claim 1, wherein the therapeutic amount of adrug condensation aerosol comprises between 2 mg and 100 mg ofhydroxyzine delivered in a single inspiration.
 15. The method accordingto claim 1, wherein the therapeutic amount of a drug condensationaerosol comprises between 5 mg and 60 mg of promethazine delivered in asingle inspiration.
 16. A method of administering a drug condensationaerosol to a patient comprising administering the drug compensationaerosol to the patient by inhalation, wherein the drug is selected fromthe group consisting of azatadine, brompheniramine, carbinoxamine,chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine,hydroxyzine and promethazine, and wherein the drug condensation aerosolis formed by heating a thin layer containing the drug, on a solidsupport, to produce a vapor of the drug, and condensing the vapor toform a condensation aerosol characterized by less than 10% drugdegradation products by weight, and an MMAD of less than 5 microns. 17.A kit for delivering a drug condensation aerosol comprising: a. a thinlayer containing the drug, on a solid support, wherein the drug isselected from the group consisting of azatadine, brompheniramine,carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine,pyrilamine, hydroxyzine and promethazine, and b. a device for providingthe condensation aerosol, wherein the condensation aerosol is formed byheating the thin layer to produce a vapor of the drug, and condensingthe vapor to form a condensation aerosol characterized by less than 10%drug degradation products by weight, and an MMAD of less than 5 microns.18. The kit according to claim 17, wherein the device comprises: a. aflow through enclosure containing the solid support, b. a power sourcethat can be activated to heat the solid support, and c. at least oneportal through which air can be drawn by inhalation, wherein activationof the power source is effective to produce a vapor of the drug, anddrawing air through the enclosure is effective to condense the vapor toform the condensation aerosol.
 19. The kit according to claim 18,wherein the heat for heating the solid support is generated by anexothermic chemical reaction.
 20. The kit according to claim 19, whereinthe exothermic chemical reaction is oxidation of combustible materials.21. The kit according to claim 18, wherein the heat for heating thesolid support is generated by passage of current through an electricalresistance element.
 22. The kit according to claim 18, wherein the solidsupport has a surface area dimensioned to accommodate a therapeutic doseof the drug.
 23. The kit according to claim 17, wherein peak plasma drugconcentration is reached in less than 0.1 hours.
 24. The kit accordingto claim 17, further including instructions for use.
 25. The methodaccording to claim 1, wherein the condensation aerosol is characterizedby an MMAD of 0.1 to 5 microns.
 26. The method according to claim 2,wherein the condensation aerosol is characterized by an MMAD of about0.2 to 3 microns.
 27. The method according to claim 16, wherein the drugis azatadine.
 28. The method according to claim 16, wherein the drug isbrompheniramine.
 29. The method according to claim 16, wherein the drugis carbinoxamine.
 30. The method according to claim 16, wherein the drugis chlorpheniramine.
 31. The method according to claim 16, wherein thedrug is clemastine.
 32. The method according to claim 16, wherein thedrug is cyproheptadine.
 33. The method according to claim 16, whereinthe drug is loratadine.
 34. The method according to claim 16, whereinthe drug is pyrilamine.
 35. The method according to claim 16, whereinthe drug is hydroxyzine.
 36. The method according to claim 16, whereinthe drug is promethazine.
 37. The kit according to claim 17, wherein thecondensation aerosol is characterized by an MMAD of less than 3 microns.38. The kit according to claim 17, wherein the condensation aerosol ischaracterized by an MMAD of 0.1 to 5 microns.
 39. The kit according toclaim 37, wherein the condensation aerosol is characterized by an MMADof about 0.2 to 3 microns.
 40. The kit according to claim 17, whereinthe drug is azatadine.
 41. The kit according to claim 17, wherein thedrug is brompheniramine.
 42. The kit according to claim 17, wherein thedrug is carbinoxamine.
 43. The kit according to claim 17, wherein thedrug is chlorpheniramine.
 44. The kit according to claim 17, wherein thedrug is clemastine.
 45. The kit according to claim 17, wherein the drugis cyproheptadine.
 46. The kit according to claim 17, wherein the drugis loratadine.
 47. The kit according to claim 17, wherein the drug ispyrilamine.
 48. The kit according to claim 17, wherein the drug ishydroxyzine.
 49. The kit according to claim 17, wherein the drug ispromethazine.
 50. The kit according to claim 18, wherein the solidsupport has a surface to mass ratio of greater than 1 cm² per gram. 51.The kit according to claim 18, wherein the solid support has a surfaceto volume ratio of greater than 100 per meter.
 52. The kit according toclaim 18, wherein the solid support is a metal foil.
 53. The kitaccording to claim 52, wherein the metal foil has a thickness of lessthan 0.25 mm.